Repeated dose toxicity comprises the adverse general
toxicological effects occurring as a result of repeated daily dosing with, or
exposure, to a substance for a specified period up to the expected lifespan of
the test species. The studies yield information on general characteristics of
the toxicity, the target organs of toxicity, the dose–response (curve) for each
toxicity endpoint, responses to toxic metabolites formed in the organism,
delayed responses, cumulative effects, the margin between toxic/non-toxic dose,
information on reversibility/irreversibility of the effect, and NOAEL (No
Observed Adverse Effect Level), NOEL (No Observed Effect Level) for toxicity.

The repeated dose study is an integral part of the data
package produced to perform quantitative risk assessment (QRA) of industrial
chemicals, cosmetic ingredients, biocides, pesticides, pharmaceuticals. The
point of departure most commonly used for systemic toxicity safety assessment
is the NOAEL which is used in the calculation of the MoS (Margin of Safety) or
MoE (Margin of Exposure).

The aim of this European project was to develop a novel
strategy for predicting chronic toxicity in the two most important target
organs affected by drugs and xenobiotics, the liver and the kidney. Advanced
culture technology, genomic, proteomic and cytomic analysis were combined to
detect the early events of cellular injury. The data generated were examined in
view of the known pathophysiological changes linked to the chronic disease.

ECVAM was part of the executive board and had an advisory
role to ensure that methods were sufficiently well developed so that they could
be considered for entering, eventually, future validation process.

Pulmonet was created with the aim to improve methodological
approaches to study lung function (such as fluid transport, secretion of
surfactant, mucous or inflammatory mediators, and barrier/ transport functions)
and dysfunction on a cellular and molecular level, gaining a better
understanding of normal lung function, toxicity of environmental compounds,
cell and tissue damage and generation of pulmonary disease. The network
consisted of experts from diverse fields, such as on lung proteins required for
host defense and reduction of surface tension (surfactant proteins), lung cell
isolation and culture, endotoxins and cell signalling, cytokines, inflammation
and immune response, and use of cell lines (such as Calu-3) for barrier
function and toxicity tests.

The ultimate goal of Predict-IV is to deliver integrated
test system/test strategy with specific biomarkers to predict repeated dose
toxicity based on in vitro data before entering in vivo testing. JRC-IHCP is a
partner in this EU project and leads activities on in vitro neurotoxicity
testing, and contributes to OMICs profiling methods and on monitoring European
efforts towards other non animal-based integrative approaches (See: Predict-IV website).

This Research Initiative is a first step to address the long
term strategic target of "Safety Evaluation Ultimately Replacing Animal
Testing (SEURAT)". It is composed of six complementary research projects
(SCR&Tox, HeMiBio DETECTIVE, COSMOS, NOTOX, ToxBank) and a coordination and
support action (COACH).

The European Commission Joint Research Centre, Institute for Health and Consumer Protection (JRC-IHCP) is a partner in SCR&Tox, DETECTIVE, COSMOS, and
COACH.